Evidence indicates that persistent viral infections of the central nervous system (CNS) can contribute to human mental disorders of unknown etiology. Borna disease virus (BDV) causes central nervous system (CNS) disease in several vertebrate species which is characterized by behavioral disturbances. Based on its unique features, BDV represents the prototype of a new virus family. Seroepidemiological data shows an association of BDV with affective disorders and schizophrenia, mental disorders with worldwide distribution and great impact in human health. This hypotheses is further supported by the detection of BDV RNA in peripheral blood mononuclear cells (PBMC) of neuropsychiatric patients, and the isolation of BDV from such PBMC. Moreover, BDV antigen and RNA have been detected in the hippocampus of autopsy brain samples from four patients who presented with major depression and memory loss. The central goal of this application is to test the hypothesis that BDV persistent infection in the human CNS is associated with affective disorders and schizophrenia, possibly contributing to the pathophysiology of these disorders. The application has two specific aims: The first aim is to determine the prevalence of BDV in the CNS of affective disorders and schizophrenia cases, and compare them with that found in other mental disorders and normal controls. Brain autopsy samples from disease and normal control cases will be analyzed for expression of BDV RNA and antigen. Viral RNA will be detected by RT-PCR and their specificity determined by Southern blot hybridization and sequencing, while BDV antigen will be detected by immunocytochemistry using an antibody to the BDV nucleoprotein. Ancillary studies will include the use of Western blot to detect antibodies to BDV in CSF and serum samples. Virus isolation will be attempted from cases found to be BDV positive. The second aim will examine the hypothesis that BDV persistence in the CNS can contribute to synaptic pathology and alterations in neuronal organization, as well as chronic astrocytosis, which could contribute to the pathophysiology of affective disorders and schizophrenia. Synaptic density and plasticity will be evaluated by examining the expression of synaptophysin and GAP-43, respectively, whereas MAP-2 expression will be used to assess dendritic organization. Double labeling experiments will be done to correlate the distribution and levels of BDV expression and severity of synaptic pathology. Astrocytosis will be assessed by analysis of GFAP expression. The studies proposed will contribute to the assessment of the potential role of BDV as an emerging human neurotropic pathogen, possibly associated with mental disorders.